Dilemmas in the diagnosis and management of osteoporosis in a patient with alkaptonuria: Successful treatment with teriparatide

Abstract Management of osteoporosis in patients with alkaptonuria can be challenging. This is the first case report confirming the effectiveness of teriparatide following zoledronic acid therapy in treating osteoporosis and preventing fragility fractures in a patient with alkaptonuria.


| INTRODUCTION
It has been recognized that osteoporosis-related fractures are common in patients with alkaptonuria (AKU). Therapy for osteoporosis in AKU is challenging since patients with AKU are susceptible to fractures despite bisphosphonate therapy. [1][2][3][4][5] Ranganath et al recently reported successful treatment of osteoporosis with teriparatide in 2 patients with AKU. 6 We report the first case of long-term follow-up of a 69-year-old woman who developed fragility fractures despite receiving bisphosphonate therapy and was successfully treated with teriparatide.

| CASE PRESENTATION
A 69-year-old female with a history of AKU was evaluated for osteoporosis. She was diagnosed with AKU at the age of 29 years when the dermatologist noted bluish conjunctival hyperpigmentation ( Figure 1A,B and Table 1). The patient experienced joint pains involving several joints and subsequently underwent joint replacements involving both knees, bilateral total hips, and bilateral shoulders. Past history included low back pain managed with celecoxib and tramadol. Family history ( Figure 2) revealed her 85-year-old sister was diagnosed with AKU, had aortic valve replacement surgery, and underwent multiple joint replacement surgeries. On examination of the head/ears/ eyes/nose/throat (HEENT): bluish black pigmentation of bilateral sclera and ears ( Figure 1A,B). Heart: normal S1 (first heart sound) and S2 (second heart sound), late peaking systolic ejection murmur heard on right parasternal area.
Hospital course of osteoporosis (see Tables 3 and 4): The patient was diagnosed with osteoporosis at the age of 56 years; Table 1 shows the baseline laboratory values prior to starting treatment for osteoporosis, Table 3 shows the history of osteoporosis treatment, and Table 4 shows the serial bone mineral density (BMD) values during the treatment with bisphosphonate therapy. Drug compliance for bisphosphonate therapy was verified by pill counting  and by the response of bone resorption markers. Despite 5 years of compliance with bisphosphonate and nitisinone therapies, she developed fragility fractures at multiple sites with minimal trauma. Following these fractures, at the age of 61 years, she was treated with teriparatide 20 mcg daily subcutaneously for the next 2 years and then received annual zoledronic acid infusions for the subsequent 5 years. Serum calcium levels were monitored closely, and the patient did not develop hypercalcemia during teriparatide treatment.
Since the initiation of teriparatide therapy, she had no further fractures for following 9 years despite a physically active life. She also continued nitisinone 2 mg orally daily since the age of 56 years and had no side effects including keratopathy.

| DISCUSSION
In AKU, mutations of a gene coding for homogentisate 1,2-dioxygenase (HGD) lead to disruption of tyrosine metabolism and result in accumulation of homogentisic acid (HGA) which results in a multisystemic disorder. The patient reported here had several of the manifestations of AKU including darkening of urine upon standing, bluish discoloration of the eyes and ears, and degenerative joint diseases involving multiple joints and the spine. [1][2][3][4][5][7][8][9][10][11] It is reported that by age 64 years, 50% of individuals with alkaptonuria may develop nephrolithiasis, 9 and the renal stone analysis usually shows calcium oxalate, phosphate, and carbonate. 7,9 However, computed tomography (CT) of the kidneys did not reveal any evidence of nephrolithiasis   in our patient. A renal stone panel in our patient showed high normal urine citrate level although calcium oxalate and calcium urate saturations were elevated. These renal stone laboratory values are consistent with the previously reported calcium oxalate stones, 9 and this is the first case report showing the urinary renal stone panel in a patient with alkaptonuria. The exact mechanism by which HGA deposition causes arthropathy is not clearly understood although it is suggested that the oxidized HGA deposits in the deeper layers of the articular cartilage may be a contributing factor. Additionally, the free radicals generated during the process of HGA oxidation may precipitate the inflammatory and degenerative processes, ultimately leading to tissue damage. 1,7,11 Lysyl hydroxylase, an enzyme located in the cartilage tissue, is inhibited by the HGA oxidation process, and this may be a contributing factor. 11 It is also possible that the bone matrix becomes more susceptible to pigmentation in response to tissue injury. 11 Several variants of the HGD gene have been reported in AKU. An HGD comprehensive gene analysis done in our patient confirmed compound heterozygous pathogenic variants, HGD c.469 + 2T>C (p.7) and HGD c.1102A>G (p.Met368Val), consistent with a diagnosis of AKU. Ascher et al 12 identified 28 novel variants of the HGD gene in 172 AKU patients, and a genotype-phenotype correlation study was performed for the three most frequent HGD variants. These investigators concluded that there was no difference in clinical symptoms, serum levels, or absolute urinary excretion of HGA. 12 Despite the lack of HGA deposition in mineralized bone matrix without tissue injury, the risk of osteoporosis in AKU patients is high. Immobility of the spine due to pain hardened calcified ochronotic intervertebral discs and ochronosis in the adjacent articular cartilage of the vertebrae may occur. However, it is interesting to note that vertebral fractures in these patients are rather rare. 13 Focal osteoporosis often leads to thinning of trabeculae and subchondral plates. Ranganath et al 4 studied 15 patients with AKU and reported a nonvertebral fracture incidence of 53.3%. Our patient had several fractures involving multiple sites even while receiving oral bisphosphonate treatment. The overestimated BMD at the lumbar spine is likely related to intervertebral disc calcification and osteophyte formation, 3 which we observed in our patient. Patients with ochronosis are more prone to fractures due to decreased BMD as seen in our patient who had ochronosis. 7,[14][15][16][17][18][19] Recent studies by Ranganath et al 18,19 showed nitisinone decreases HGA in AKU and reduces the rate of progression of AKU, mainly seen as combined ear and ocular bluish color progression. However, these investigators did not report on the effect of nitisinone on the skeletal manifestations. Since we did not measure the progression of ocular and ear ochronosis serially, it is difficult to assess the effect of this drug on ochronosis of the eye and ears. Additionally, nitisinone apparently had no effect on the progression of the skeletal manifestations of AKU in our patient. Our patient received nitisinone at the age of 56 years, and it is possible that treatment at an earlier age will be more effective.

BMD T-S Z-S BMD T-S Z-S BMD T-S Z-S BMD T-S Z-
Ranganath et al. 6 reported that DXA (dual-energy X-ray absorptiometry) scan is not reliable in AKU patients due to extensive calcification of intervertebral discs as well as the extensive degenerative arthritis or joint replacements. In our patient, although an initial and serial DXA scans showed normal BMD at the lumbar spine, the BMD was likely falsely elevated; however, her hip BMD done at the age of 61 years showed osteoporosis (femoral neck T-score −2.9). Follow-up DXA scans could not be done at this site due to the joint replacement. Thus, the dilemmas involved in diagnosing osteoporosis seen in our patient with AKU are similar to those skeletal disorders such as diffuse interosseous skeletal hyperostosis (DISH) and ankylosing spondylitis. Alternative sites such as forearm BMD may have to be utilized. Alternatively, CT lumbar spine BMD measurements may be used. 9 More recently, trabecular bone scan (TBS) has been utilized to measure BMD, although the diagnostic sensitivity of TBS in AKU remains to be established.
Management of osteoporosis in AKU patients thus presents several challenges to the clinician. 4,18,19 Despite the appropriate use of bisphosphonate therapy initially, our patient developed multiple fragility fractures, confirming the failure to bisphosphonate therapy. Aliberti et al 4 also concluded that there is no clinically significant difference in BMD after 2 years of bisphosphonate treatment. Similarly, nitisinone treatment does not improve osteoporosis or prevent fragility fractures associated with osteoporosis in these patients. 4 After 5 years of treatment with bisphosphonates, our patient was treated with teriparatide. More recently, Ranganath et al in 2021 have also demonstrated the effectiveness of teriparatide in 2 AKU patients. 6 Thus, our patient represents the third AKU patient with bisphosphonate-resistant osteoporosis who was treated successfully with teriparatide. The anabolic actions of PTH occur because of its direct effects on cells of the osteoblast lineage and indirect effects through the induction of IGF-I (insulin-like growth factor-1) and the suppression of sclerostin with the consequent enhancement of Wnt signaling and by suppressing Notch signaling. 20 In conclusion, we recommend that osteoporosis in AKU be initially treated with teriparatide and later by intravenous zoledronic acid. Further studies involving larger number of patients are needed.

AUTHOR CONTRIBUTIONS
All authors equally accessed the data and contributed to the preparation of the manuscript. IE and MKMS drafted the manuscript. TDH and NOV critically reviewed and edited the manuscript. JPS reviewed the manuscript and provided the genetic counseling.